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- Title
Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer.
- Authors
Takahashi, Ryota; Ijichi, Hideaki; Sano, Makoto; Miyabayashi, Koji; Mohri, Dai; Kim, Jinsuk; Kimura, Gen; Nakatsuka, Takuma; Fujiwara, Hiroaki; Yamamoto, Keisuke; Kudo, Yotaro; Tanaka, Yasuo; Tateishi, Keisuke; Nakai, Yousuke; Morishita, Yasuyuki; Soma, Katsura; Takeda, Norihiko; Moses, Harold L.; Isayama, Hiroyuki; Koike, Kazuhiko
- Abstract
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
- Subjects
VASCULAR cell adhesion molecule-1; PANCREATIC cancer treatment; CANCER chemotherapy; MACROPHAGES; DRUG resistance in cancer cells
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, pN.PAG
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-78320-3